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Ligation of the inhibitory receptor NKG2A by its ligand HLA-E negatively regulates the activation of natural killer (NK) cells, as well as subsets of CD8+ T cells and innate T cell populations. NKG2A has recently become a novel immune checkpoint target for the treatment of cancer and direct antibody mediated blockade of NKG2A function is currently under assessment in two phase 3 clinical trials. In addition to direct targeting, the NKG2A:HLA-E axis can also be disrupted indirectly via multiple different targeted cancer agents that were not previously recognised to possess immunomodulatory properties. Increased understanding of immune cell modulation by targeted cancer therapies will allow for the design of rational and more efficacious drug combination strategies to improve cancer patient outcomes. In this review, we summarise and discuss the various strategies currently in development which either directly or indirectly disrupt the NKG2A:HLA-E interaction to enhance NK cell activation against cancer.

The first-in-class inhibitor of exportin-1 (XPO1) selinexor is currently under clinical investigation in combination with the BTK inhibitor ibrutinib for patients with chronic lymphocytic leukaemia (CLL) or non-Hodgkin lymphoma. Selinexor induces apoptosis of tumour cells through nuclear retention of tumour suppressor proteins and has also recently been described to modulate natural killer (NK) cell and T cell cytotoxicity against lymphoma cells. Here, we demonstrate that XPO1 inhibition enhances NK cell effector function against primary CLL cells via downregulation of HLA-E and upregulation of TRAIL death receptors DR4 and DR5. Furthermore, selinexor potentiates NK cell activation against CLL cells in combination with several approved treatments; acalabrutinib, rituximab and obinutuzumab. We further demonstrate that lymph node associated signals (IL-4 + CD40L) inhibit NK cell activation against CLL cells via upregulation of HLA-E, and that inhibition of XPO1 can overcome this protective effect. These findings allow for the design of more efficacious combination strategies to harness NK cell effector functions against CLL.

Guidelines for the management of patients with invasive candidiasis and mucosal candidiasis were prepared by an Expert Panel of the Infectious Diseases Society of America. These updated guidelines replace the previous guidelines published in the 15 January 2004 issue of Clinical Infectious Diseases and are intended for use by health care providers who care for patients who either have or are at risk of these infections. Since 2004, several new antifungal agents have become available, and several new studies have been published relating to the treatment of candidemia, other forms of invasive candidiasis, and mucosal disease, including oropharyngeal and esophageal candidiasis. There are also recent prospective data on the prevention of invasive candidiasis in high-risk neonates and adults and on the empiric treatment of suspected invasive candidiasis in adults. This new information is incorporated into this revised document.

A genome-wide association scan in individuals with Crohn's disease by the Wellcome Trust Case Control Consortium detected strong association at four novel loci. We tested 37 SNPs from these and other loci for association in an independent case-control sample. We obtained replication for the autophagy-inducing IRGM gene on chromosome 5q33.1 (replication P = 6.6 × 10 −4 , combined P = 2.1 × 10 −10 ) and for nine other loci, including NKX2-3 , PTPN2 and gene deserts on chromosomes 1q and 5p13.

Routinely collected data from large population health surveys linked to chronic disease outcomes create an opportunity to develop more complex risk-prediction algorithms. We developed a predictive algorithm to estimate 5-year risk of incident cardiovascular disease in the community setting. We derived the Cardiovascular Disease Population Risk Tool (CVDPoRT) using prospectively collected data from Ontario respondents of the Canadian Community Health Surveys, representing 98% of the Ontario population (survey years 2001 to 2007; follow-up from 2001 to 2012) linked to hospital admission and vital statistics databases. Predictors included body mass index, hypertension, diabetes, and multiple behavioural, demographic and general health risk factors. The primary outcome was the first major cardiovascular event resulting in hospital admission or death. Death from a noncardiovascular cause was considered a competing risk. We included 104 219 respondents aged 20 to 105 years. There were 3709 cardiovascular events and 818 478 person-years follow-up in the combined derivation and validation cohorts (5-year cumulative incidence function, men: 0.026, 95% confidence interval [CI] 0.025–0.028; women: 0.018, 95% 0.017–0.019). The final CVDPoRT algorithm contained 12 variables, was discriminating (men: C statistic 0.82, 95% CI 0.81–0.83; women: 0.86, 95% CI 0.85–0.87) and was well-calibrated in the overall population (5-year observed cumulative incidence function v. predicted risk, men: 0.28%; women: 0.38%) and in nearly all predefined policy-relevant subgroups (206 of 208 groups). The CVDPoRT algorithm can accurately discriminate cardiovascular disease risk for a wide range of health profiles without the aid of clinical measures. Such algorithms hold potential to support precision medicine for individual or population uses. Study registration: ClinicalTrials.gov, no. NCT02267447

We evaluated the feasibility and efficacy of a 2-week training programme comprising resistance vibration exercise (RVE) without and with artificial gravity (AG). Participants (n = 24) were divided into three groups: (i) URVE: upright loaded squat exercise; (ii) HRVE: horizontal loaded squat exercise; and (iii) AGRVE: loaded squat exercise conducted on a short-arm human centrifuge. All participants followed the same protocol and were exposed to the same ground reaction force, whilst performing exercise comprising bilateral squats, triple extension squats and single/bilateral calf raises. Before and after the 2-week training period, we measured thigh and calf muscle strength with isokinetic dynamometry, muscular power with a jump test, volume with functional muscle magnetic resonance imaging, and body composition with dual-energy X-ray absorptiometry. All groups showed significant improvements in eight-repetition maximum squat strength (P < 0.0001, G > 0.80), whilst only the AGRVE group demonstrated a small effect in jump height (G = 0.26). The AGRVE group significantly increased knee extension and flexion maximum voluntary contraction (MVC), with no comparable changes in the HRVE or URVE groups. The AGRVE group increased total thigh muscle volume (P = 0.03), with notable hypertrophy in the vastus medialis, semitendinosus, and vastus intermedius muscles. These findings demonstrate that AGRVE is significantly superior to HRVE and URVE in enhancing knee MVC and thigh muscle volume, thus indicating that artificial gravity improves the outcome of resistance vibration exercise in ambulatory participants.

We report results of a nonsynonymous SNP scan for ulcerative colitis and identify a previously unknown susceptibility locus at ECM1 . We also show that several risk loci are common to ulcerative colitis and Crohn's disease ( IL23R , IL12B , HLA , NKX2-3 and MST1 ), whereas autophagy genes ATG16L1 and IRGM , along with NOD2 (also known as CARD15 ), are specific for Crohn's disease. These data provide the first detailed illustration of the genetic relationship between these common inflammatory bowel diseases.

Remarkable progress in molecular analyses has improved our understanding of the evolution of cancer cells toward immune escape 1 – 5 . However, the spatial configurations of immune and stromal cells, which may shed light on the evolution of immune escape across tumor geographical locations, remain unaddressed. We integrated multiregion exome and RNA-sequencing (RNA-seq) data with spatial histology mapped by deep learning in 100 patients with non-small cell lung cancer from the TRACERx cohort 6 . Cancer subclones derived from immune cold regions were more closely related in mutation space, diversifying more recently than subclones from immune hot regions. In TRACERx and in an independent multisample cohort of 970 patients with lung adenocarcinoma, tumors with more than one immune cold region had a higher risk of relapse, independently of tumor size, stage and number of samples per patient. In lung adenocarcinoma, but not lung squamous cell carcinoma, geometrical irregularity and complexity of the cancer–stromal cell interface significantly increased in tumor regions without disruption of antigen presentation. Decreased lymphocyte accumulation in adjacent stroma was observed in tumors with low clonal neoantigen burden. Collectively, immune geospatial variability elucidates tumor ecological constraints that may shape the emergence of immune-evading subclones and aggressive clinical phenotypes. Multiregion spatial histology, exome and transcriptome data from patients with non-small cell lung cancer suggest that cancer subclones from immune cold regions diversify later than subclones from immune hot regions

Approximately 50% of patients with early-stage non-small-cell lung cancer (NSCLC) who undergo surgery with curative intent will relapse within 5 years1,2. Detection of circulating tumor cells (CTCs) at the time of surgery may represent a tool to identify patients at higher risk of recurrence for whom more frequent monitoring is advised. Here we asked whether CellSearch-detected pulmonary venous CTCs (PV-CTCs) at surgical resection of early-stage NSCLC represent subclones responsible for subsequent disease relapse. PV-CTCs were detected in 48% of 100 patients enrolled into the TRACERx study3, were associated with lung-cancer-specific relapse and remained an independent predictor of relapse in multivariate analysis adjusted for tumor stage. In a case study, genomic profiling of single PV-CTCs collected at surgery revealed higher mutation overlap with metastasis detected 10 months later (91%) than with the primary tumor (79%), suggesting that early-disseminating PV-CTCs were responsible for disease relapse. Together, PV-CTC enumeration and genomic profiling highlight the potential of PV-CTCs as early predictors of NSCLC recurrence after surgery. However, the limited sensitivity of PV-CTCs in predicting relapse suggests that further studies using a larger, independent cohort are warranted to confirm and better define the potential clinical utility of PV-CTCs in early-stage NSCLC.Pulmonary venous tumor cells disseminating before tumor resection are heterogeneous, predict relapse and seed future metastasis of lung cancer

Somatic mutations together with immunoediting drive extensive heterogeneity within non-small-cell lung cancer (NSCLC). Herein we examine heterogeneity of the T cell antigen receptor (TCR) repertoire. The number of TCR sequences selectively expanded in tumors varies within and between tumors and correlates with the number of nonsynonymous mutations. Expanded TCRs can be subdivided into TCRs found in all tumor regions (ubiquitous) and those present in a subset of regions (regional). The number of ubiquitous and regional TCRs correlates with the number of ubiquitous and regional nonsynonymous mutations, respectively. Expanded TCRs form part of clusters of TCRs of similar sequence, suggestive of a spatially constrained antigen-driven process. CD8+ tumor-infiltrating lymphocytes harboring ubiquitous TCRs display a dysfunctional tissue-resident phenotype. Ubiquitous TCRs are preferentially detected in the blood at the time of tumor resection as compared to routine follow-up. These findings highlight a noninvasive method to identify and track relevant tumor-reactive TCRs for use in adoptive T cell immunotherapy.A survey of T cell repertoire evolution in the tumors, healthy tissue and blood of patients with early-stage untreated lung cancer offers an opportunity to monitor and identify neoantigen-specific T cells for personalized immunotherapy.